Until the mid-1980s, the accepted treatment for atherosclerosis, i.e., narrowing of the coronary artery(ies) was coronary by-pass surgery. While effective and having evolved to a relatively high degree of safety for such an invasive procedure, by-pass surgery still involves serious potential complications and in the best of cases an extended recovery period.
With the advent of percutaneous transluminal coronary angioplasty (PTCA) in 1977, the scene changed dramatically. Using catheter techniques originally developed for heart exploration, inflatable balloons were employed to re-open occluded regions in arteries. The procedure was relatively non-invasive, took a very short time compared to by-pass surgery and the recovery time was minimal. However, PTCA brought with it another problem, elastic recoil of the stretched arterial wall which could undo much of what was accomplished and, in addition, failed to satisfactorily ameliorate another problem, restenosis, the re-clogging of the treated artery.
The next improvement, advanced in the mid-1980s was use of a stent to hold the vessel walls apart after PTCA. This for all intents and purposes put an end to recoil but did not entirely resolve the issue of restenosis. That is, prior to the introduction of stents, restenosis occurred in from 30-50% of patients undergoing PTCA. Stenting reduced this to about 15-20%, much improved but still more than desirable.
In 2003, drug-eluting stents or DESs were introduced. The drugs initially employed with the DES were cytostatic compounds, compounds that curtailed the proliferation of cells that resulted in restenosis. The occurrence of restenosis was thereby reduced to about 5-7%, a relatively acceptable figure. Today, the DES is the default the industry standard to treatment of atherosclerosis and is rapidly gaining favor for treatment of stenoses of blood vessels other than coronary arteries such as peripheral angioplasty of the femoral artery.
One of the key criteria of DESs is selection of a polymer or blend of polymers to be used in a drug reservoir layer, a rate-controlling layer, a protective topcoat layer, etc. If a biostable polymer is selected, i.e., a polymer that does not significantly decompose in a patient's body, their chemical composition is often not of significant concern since they are not intended to break down and enter the patient's system. On the other hand, currently biodegradable polymers are preferred for many applications because their ability to decompose in a biological environment confers on them a number of desirable characteristics. For example, the fact that a polymer will biodegrade and can eventually be essentially completely eliminated from a patient's body can avoid the need to invasively remove a DES after its job is done. In addition, by judicious choice of biodegradable polymer, e.g., selecting one that bio-erodes by bulk erosion or one that bio-erodes by surface erosion, the properties of the polymer can be used as an added tool for the fine-tuning of the release rate of a drug.
Of course, if a polymer is going to degrade in a patient's body, it is imperative that it be biocompatible, that is, that its degradation products do no harm to the patient. This requires careful attention to the chemistry of the polymer and the properties of its degradation products. A great deal of work has gone into the effort to find suitable biodegradable polymers and one class of such polymers that is exhibiting particularly desirable properties in terms of biodegradation, biocompatibility, drug compatibility and, generally, the range of properties that can be engineered into the polymer by judicious selection their constitutional units is the poly(ester-amide) family of polymers.
As currently employed, however, poly(ester-amide)s tend generally to be rather soft and quite permeable to many if not most drugs, which limits their application in DESs to some extent. There is a need for polymers that are stronger, tougher and less permeable than those currently in use while still maintaining the other beneficial characteristics of the class.
Such polymers would have use in other areas of drug delivery including particles for drug delivery. Particles including a drug can be used for local drug delivery. Local drug delivery has advantages over systemic delivery.
Specifically, by avoiding the gastrointestinal tract, the drug is not subject to the first pass metabolism in the liver, although it will still be subject to metabolism by enzymes that exist outside the gastrointestinal tract. In addition, by delivering the drug to the site where it is needed, there is a potential to obtain higher concentrations of drug at the site since systemic delivery to obtain the same local concentration may result in toxicity or adverse events. It is often preferred that polymers used to make drug delivery particles be biodegradable. This avoids the issue of removal which may not even be feasible for small particles.
The current invention provides polymers, poly(ester-amide) polymers and poly(amide) polymers, that are stronger, tougher and more compatible with active pharmaceutical ingredients than those currently in use while still maintaining the other beneficial characteristics of the class of poly(ester-amide)s. The polymers may be used for drug delivery coatings and drug delivery particles.